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Aspects of radiation therapy
C H A P T E R
14 Aspects of radiation therapy O U T L I N E 14.1 General 376 14.1.1 Units of therapeutic radiation and absorption 376 14.1.2 Aspects of kinds of damage; differences according to species and kinds of cells 376 (a) Species 377 (b) Cells 378 14.1.3 Oxygen effect 378 14.1.4 Hyperthermia as a possible adjunct in radiation and chemotherapy distinct from thermal ablation 378 14.1.5 Radiation therapy enhancing metastasis 378 14.1.6 Specific issues in radiations acting on genomic stability in cells 379 14.2 Aspects of particular forms of radiation therapy 379 14.2.1 Electron beam radiation therapies 379 14.2.2 Nuclear particle beams 379 (a) Protons in comparison with high energy radiations 379 (b) Neutrons 381
The history of radiation therapy, like that of radiology, began shortly after the discovery of X-rays by Roentgen in 1895. Two modes were
Principles of Tumors https://doi.org/10.1016/B978-0-12-816920-9.00014-6
(c) Helium nuclei (a-rays) (d) “Heavy” ions: carbon nuclei
14.2.3 Radio-sensitizers and protectors 14.2.4 Aspects of applications in the clinic (a) Anatomical precision (b) Treatment of regular side effects (c) Limitations to total doses of radiation therapy (d) Protection of radiation therapy staff
381 381
381 381 381 382 382 383
14.3 Recommended regimens for common malignancies 383 14.3.1 Carcinoma of lung 383 14.3.2 Carcinoma of the colon and rectum383 14.3.3 Carcinoma of breast 383 14.3.4 Carcinoma of prostate 385 14.3.5 Hematological malignancies 386 14.3.6 Gamma knife radiosurgery for tumor deposits in the brain 386 References
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quickly developed: administration by X-ray from electric generators and administration by local application of radium salts [1,2].
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The main principles of radiotherapy for tumors were established in the early 20th century:
tissue as well as the energy carried by the particles of the radiation.
(i) Different sensitivities of different types of tumors (ii) Greater efficacy when given in split dosesd“fractionation” (see in Chapter 13) (iii) Different frequencies of relapses for different types of tumors (iv) Absence of any single target, or cancerspecific target of radiations in tumor cells. Because of this, effective radiotherapy depends on the tumor cells being more sensitive to the treatment than normal cells (v) Cumulative therapeutic limit for normal tissues. Patients cannot tolerate radiotherapy above particular total lifetime doses (see Section 13.1.10) (vi) Predictable side effects.
Incident radiation energy is quantitated in terms of the “Roentgen,” which is the amount of radiation necessary to create by ionization of 1 esu (electrostatic unit) of electricity in 1 cm3 of air under standard conditions. Absorbed radiation energy in any structure can be referred to in units called “rads” (radiation absorbed dose), or as more often as “Gray” (100 rads ¼ 1Gy). To account for differences between tissues (see Appendix A1.1.4), the “rem” (radiation equivalent in man) was devised. It is a complex average of the rads of different tissues and is used in studies of human radiation tolerances and damage. The unit now widely used is the “Sievert” (100rem ¼ 1 Sievert). “Linear energy transfer” (LET) is the rate of energy transfer per unit distance (e.g., keV/ mm) that a particular kind of radiation deposits in a particular matter or structure. It is mainly used in experimental studies of radiation damage. The relationships between LET and RBE (relative biological effect) differ between different tissues. This is made more difficult by problems of defining and quantitating “effect” in different biological systems. Therapeutically, radiations generally only affect cells exposed to them. They have little or no effect on cells outside the irradiated field, except perhaps by the “bystander effect” [4]. Recurrences may therefore arise for reasons similar to those seen after attempted cure by surgical resection (see Fig. 14.1).
With the invention of higher-energy X-ray machines, radium applications and other isotope methods fell into disuse, although, recently, the principle has been reintroduced as “brachytherapy” for treatment especially of carcinoma of the prostate [3] and some other organs. This chapter describes the features which are important for their therapeutic uses.
14.1 General 14.1.1 Units of therapeutic radiation and absorption In physics, energy can be indicated in terms of the electron volt (eV), being the energy absorbed or lost by the charge on an electron moved by 1 volt of electric potential difference. In medicine, units of energy deposition have been derived in relation to tissue damage reflecting that (i) Only absorbed energy has any effect on the tissues. (ii) The proportion of the energy in the incident radiations which is absorbed by the tissue or part of the body depends on the kind of
14.1.2 Aspects of kinds of damage; differences according to species and kinds of cells Radiations in different doses can produce most of the known genopathic and nongenopathic effects (see in Appendix A7). Commonly in high short-term dosages, radiations regularly cause
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14.1 General
Incident rays
Absorption and scatter of rays Air
30cm of tissue
Photons Ultraviolet rays: Penetrate a few mm; no scatter of secondary rays ‘Soft’ X-rays: Superficial maximum absorbance; penetrate 10-20 cm, no significant scatter of secondary rays ‘Hard’ X-rays: Deeper maximum absorbance, pass through human body (as for diagnostic imaging); moderate scatter. Gamma rays: Deeper maximum absorbance, considerable penetration; greater scatter.
= depth at which maximum rate of absorption/unit length of path occurs.
“Scatter”
“Scatter” and secondary photonic radiations
Electrons Penetration up to 5 cm depending on energy. No scatter. Protons 20-30 cm penetration, Most energy deposited at termination (similar shape as ‘Bragg peak’ of photons in air), Litter scatter of the protons occurs, but seconday photonic radiations are generated.
FIGURE 14.1
Secondary photonic radiations
Absorption, penetration, and scatter for different particles and different energies (EVs) in water (most tissues
are similar).
nongenopathic effects, especially inflammation of tissues and acute cell death. At lower doses given over longer periods of time, radiations cause mild inflammation and tissue atrophy. Many of these effects are variable between the different species which are used experimentally. (a) Species There are enormous differences in the radioresistance of species according to evolutionary complexity (see also Appendix A3.5.1). There is
a well-recognized ascending order of radiosensitivity from certain bacteria, through unicellular organisms such as amebae, invertebrates, and vertebrates, and then mammals, which are the most sensitive organisms. Within each category of organisms, strains have been developed by in-breeding which have greater or lesser degrees of radio-sensitivity. This indicates that some genomic factor(s), probably acting through a gene product, are associated with radiosensitivity.
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(b) Cells In general, the most sensitive cells are those in which fully specialized versions are continuously produced from local tissue stem cells. These “labile tissues” include the bone marrow and gastrointestinal epithelium (see also Appendix A1.3.3). The least sensitive cells are those of tissues which do not depend on a specific stem cell population. These “stable” kinds of cells include fibrocytes and adipocytes (see Appendix A1.4.1). The mitotic rate is thought to be a major factor in these differences [5].
14.1.3 Oxygen effect In the late 1940s, it was found that oxygenation enhances chromosomal aberrations in irradiated cells [6]. Other studies showed that in many models, cell killing due to radiation therapy is increased in hyperoxic conditions [7]. This is consistent with oxygen being the most important atom from which reactive species can be generated by radiation therapy (see Section 4.3). It should be noted that oxygen effects are only seen with radiation therapies. There is no oxygen effect with any of the common cytotoxic drugs used in nonsurgical anticancer therapy. These agents do not use oxygen as an intermediary source of toxic products. Attempts have been made to enhance tumor cell sensitivity by hyperbaric oxygen treatment to the patient. The results have generally been disappointing, although interest for these procedures continues [7]. Hypoxia induces a variety of responses in cells. One response is production of a transcription factor (hypoxia-inducible factor 1, HIF-1) which enhances production of a number of other proteins. Inhibitors of HIF-1 are potentially useful enhancers of radiation-induced cell killing [8]. As another factor, hypoxic cells may lack energy due to deficiencies in the respiratory enzyme cycle. These cells, although not dead,
may be subviable/under “cell stress” (see Appendix A7.1.7). For these cells, oxygen therapy may not assist in limiting tumor cell growth.
14.1.4 Hyperthermia as a possible adjunct in radiation and chemotherapy distinct from thermal ablation Temperatures in the range 40e45 C sensitize cells to radiations and chemotherapy [9,10]. For radiation therapy, possible mechanisms may include the following: (i) The tissue-heating effect of radiations raises the temperature in the tumor masses to the lethal range (above 45 C) and (ii) Increased ionization of atoms occurs because the electron-energizing effects of radiations are greater at higher temperatures. In relation to drugs, the chemical reactions of these agents with cellular macromolecules may be increased by increased temperatures. As a different form of treatment, raising tumor temperature over 45 C kills all cells directly and is used in the procedure known as thermal ablation, to destroy tumors [11], including in situ tumors.
14.1.5 Radiation therapy enhancing metastasis Radiation therapy induces acute inflammation in all vascular tissues (see in Appendix A7). Blood vessels and lymphatic vessels dilate and more fluid flows through them. Any tumor cells in those vessels are therefore more likely to be carried along to sites of metastasis. Radiation therapy is known to increase the numbers of circulating tumor cells [12]. If those cells derive from the irradiated tumor, they are likely to be dead, and of no consequence. However, some of the cells may be in transit outside the radiation field and be viable. These cells could then be flushed to the systemic circulation by the
14.2 Aspects of particular forms of radiation therapy
inflammatory exudates more rapidly than they would be otherwise. In this, it may be remembered that radiations only affect the cells which are exposed to them, although in some experimental conditions, a “by-stander effect” can be demonstrated [13]. This could kill cells in transit outside the radiation field. Recently, it has been suggested that radiation therapy can enhance the spread of metastases in the body [14]. The issue could be investigated further, possibly by assessing the viability of the tumor cells circulating postradiation treatment.
14.1.6 Specific issues in radiations acting on genomic stability in cells It has long been known that radiations can induce genomic events, such as chromosomal aberrations and heritable phenotypic changes (mutations) [15]. However, the idea that radiation administered to parent cells could lead to progressive genomic instability in daughter cells is relatively recent [16e18]. Genomic instability might usefully increase tumor cell loss in the short term. However, it might later lead to radio-resistant strains in surviving cells, with radiation- and chemical resistance, and even overall shorter patient survival [19].
14.2 Aspects of particular forms of radiation therapy 14.2.1 Electron beam radiation therapies Electrons in beams have only slight penetrance of tissues but are useful against some superficial skin tumors [20]. Electrons are the effective agency of the isotope used in treatment of thyroid cancers. Iodine125 decays into tellurium with the release of eight low energy electrons, but not gamma rays. The same isotope is also used for brachytherapy (direct introduction into tumor masses of sealed sources of radiation) for carcinoma of
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the prostate. This isotope of iodine is cytotoxic and causes chromosomal aberrations but is not known to be carcinogenic (cf 131I, which emits gamma rays and beta particles).
14.2.2 Nuclear particle beams For a given amount of absorbed energy, nuclear particle radiations cause more tissue damage than photonic radiations. This has created interest in their possible superiority as therapeutic agents against tumors. Machines have been developed to emit protons, neutrons, helium nuclei (a rays), and carbon nuclei in beams. However, at the time of writing, only protonbeam irradiation is being used regularly for tumor therapy. In the United States, there are 14 operative proton therapy centers and a further 10 are under construction [21]. There is a small number in the United Kingdom and elsewhere. Only approximately 1% of cancers are suitable to this mode of treatment. There is little convincing evidence that for many patients, the treatment is significantly more effective than conventional photonic radiation therapy [22]. (a) Protons in comparison with high energy radiations Protons deposit their energy in broader tracks but have lower penetrations of tissues than photons [21e24]. The benefit of beams of photons over beams of high-energy photons lies in the fact that in tissues, protons deliver energy with a peak at a particular depth (often referred to as a “Bragg peak,” while electron beams deposit energy in a slowly attenuating distribution with depth (see Fig. 14.1)). When used for treating tumors, the proton beams are adjusted so that peak energy deposition occurs in the tumor. Multiple portals are generally used (from 2 to 4) [25]. The existence of the peak results in relatively little damage to the tissues deep to the tumor. As mentioned above, photons cause greater damage to tissues compared with electrons for
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the same amount of deposited energy. This phenomenon can be understood in terms of the absorption of energy by the two forms of radiation. Because photons have low masses, the ejection of an electron from an outer shell of an atom probably requires approximately eight photons of sufficient energy moving in the same direction to strike within a short period of time (Fig. 14.2). The energy of these photons is absorbed in the one ionization event. Other ionizing events are scattered at random in the tissue.
Photons
On the other hand, due to their relatively high mass, protons only lose part of their energy in an ionizing event. After one such event, a proton can continue in its path causing multiple lesions in a line. This line can include sites in the one macromolecule, so that this clustered damage causes greater effects (Fig. 14.2). As a result, proton beams inflict more chromosomal damage and more lethality per unit energy deposited, compared with photonic radiations [21]. All nuclear particle rays can displace nuclear particles from irradiated atoms, especially
Protons
At level of electron shell
Outer electron energy level of atom Additive effects of at least eight high energy photons (as in X-rays and gamma rays, are required to ionize an atom (in biology, mainly of oxygen)
A single energized nuclear particle is sufficient to ionize an atom (in biology, mainly of oxygen)
At level of molecules Direction of rays
The energy of the photons is absorbed by the ionizing event, so that these photons cause little further damage. Low numbers of ionizing events in a molecule may not affect its structure, so that the function of the complex of which it is part may not be affected.
FIGURE 14.2
Direction of rays
The energy of the proton is only slightly reduced by the ionizing collision, so that it continues in a path causing further ionizations. High numbers of ionizing events in a molecule are likely to affect its structure, so that the function of a complex of which it is part may be affected.
Basis of different biological effects of photonic and nuclear particle radiations.
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“secondary neutrons.” The significance of this is at present unclear [26].
Bronchoscope
Oesophagus (gullet)
(b) Neutrons These rays, especially with high energy levels (“fast neutrons”), have less penetration of tissues but inflict more damage on tissues for the energy deposited than X-rays. In clinical trials, neutron beams produced more damage to normal tissues than X-rays, and without better effects on the tumor tissues [27]. (c) Helium nuclei (a-rays) These rays have very low penetration of air and tissues and are used in clinical practice via administered isotopes rather than as beams [28]. (d) “Heavy” ions: carbon nuclei These are not currently in wide use and are undergoing trials in a few centers only. At the time of writing, their superiority over X-ray therapies is unclear [25].
14.2.3 Radio-sensitizers and protectors A variety of physical agents (e.g., heat and chemicals) have been suggested to assist cell killing by radiation therapy. They include conventional cytotoxic drugs, as well as those which act through hypoxia-related phenomena [7,29]. Another group comprises inhibitors such as misonidazole, of radical-scavenging chemicals, especially thiols. Recently, metal-containing nanoparticles have been studied in this role [30] (Fig. 14.3).
14.2.4 Aspects of applications in the clinic (a) Anatomical precision The principle of radiation therapy is to deliver the maximum dose of radiation to the tumor cells for the minimum damage to normal tissues.
Trachea (windpipe)
Catheter Radioactive source Tumour
FIGURE 14.3 Internally administered radiation therapy. Source: WikiCommons, Cancer Research UK.
The precision of delivery of the radiations depends on accurate prior knowledge of the anatomical extent of the tumor. This involves understanding of the shape of the tumor mass in three dimensions. However, the demarcation between the tumor and the adjacent apparently normal tissue may be blurred because there may be micrometastases and intravascular tumor deposits beyond the macroscopic (and imaging) margins of the main tumor mass (Fig. 14.4). In practice, anatomical precision of radiation delivery from inserted pellets of radio-isotopes directly into tumor tissue (“brachytherapy”) is reasonably easy. However, for external beam irradiation, complicated equipment is required. In a typical machine, the source of the beam is located on circular gantry, can be rotated around the patient’s body, and as well, can be moved up and down (toward the head or feet). The beam source can also be angled in any direction with the “cylinder” of the head-to-foot movement of the gantry. Thus, potentially, every part of the body can be irradiated from any angle. The beam can be modified in various ways and changed in shape
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(mainly made more oval) by alterations in the collimator of the beam source [31]. The most modern machines have a computerized tomographic (“CT”) or magnetic resonance imaging (“MRI”) function added to the radiation-source function. With these, it is possible to deliver radiations of the required dose according to the detailed threedimensional images of the tumor in the patient. (b) Treatment of regular side effects Regular local side effects occur because damage to untargeted adjacent tissue is a regular side effect of all radiation therapies. Damage to normal tissue can occur (i) Between the beam source and the tumor, (ii) Beyond the tumor, and also (iii) To the sides of the tumor, by way of “scatter” of radiations. Regular systemic side effects occur because most forms of cytotoxic damage to parts of the body result in tissue breakdown products
entering the circulation. These substances can cause mild malaise and nausea (see in Section 10.4), for example, in myocardial infarction. In radiation therapy, fatigue, nausea, vomiting, and malaise occur in all patients, and often in severe degrees [32]. The mechanisms are not understood. Radiation-killed cells and tissues may release products of greater potency than from unirradiated dead cells, due to the degrees of denaturation of the substances which may occur. Various inflammatory mediators, including 5hydroxytryptamine [33], may play roles in these side effects. Various antinausea drugs and corticosteroids are often given for relief of these symptoms. They do not affect the efficacy of the radiation treatment. (c) Limitations to total doses of radiation therapy These can be classified as local and systemic (see also Section 13.1.11). Local limiting factors to total dose of radiation therapy mainly relate
= recurrent mass of matastatic tumor Focal extension of tumor mass
Other Organs
In principle, this ‘ablative’ radiotherapy has similar limitations to those of surgery: tumor outside the field of irradiation is little affected.
FIGURE 14.4
Sources of recurrences after radiation therapy.
14.3 Recommended regimens for common malignancies
to the site of the tumor. In cases in which the tumor is close to a vital organ or structure in the path of the proposed radiation beams, too much radiation may damage the vital structure. Any concurrent disease in those organs (for example, previous glomerular disease in a kidney in or near the radiation field) must be taken into account. Systemic limiting factors to total possible therapeutic dose include the presence of any other diseases, such as emphysema, heart disease, or renal failure, which would make the patient less able to tolerate radiation therapy.
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14.3.2 Carcinoma of the colon and rectum Radiation therapy to treat colon cancer in selected cases: (i) Before surgery (along with chemo) to help shrink a tumor and make it easier to remove. (ii) After surgery, if the cancer has attached to an internal organ or the peritoneum. (iii) Rarely, it can be given just before closing the abdomen, to the tumor bed. (iv) Along with chemotherapy as the primary treatment if the patient has comorbidities preventing surgery [36].
(d) Protection of radiation therapy staff Staff members working in radiation therapy departments are often long-term employees. All staff members have protective shielding when in treatment areas and wear exposure monitors when at work. The question of acceptable long-term exposure to radiations is an important, but to a degree controversial, issue (see, e.g., Ref. [34]).
14.3 Recommended regimens for common malignancies 14.3.1 Carcinoma of lung Radiation is most effective against smallcelled carcinoma. In almost all institutions, external beam radiotherapy doses are guided by CT imaging (see in Chapter 11) to deliver the optimum dose to the tumor and the least radiation to normal tissues (intensity-modulated radiation therapy/IMRT). With some machines, it is possible to deliver higher doses (stereotactic body radiation therapydSBRT). With these techniques, the total dose depends directly on the volume of tumor [35] (Fig. 14.5).
14.3.3 Carcinoma of breast Radiations can be delivered by external beam or isotope insertions. It can be given as the primary treatment, but most commonly is used as a postsurgical adjuvant therapy to the bed of the resection (the chest wall following mastectomy). There can be difficulty with anatomical precision, because breast cancers can spread along ducts without forming a mass and in addition be multifocal. The tumor must be unresectable and tethered to prevent movement during irradiation. Radiation pneumonitis is a common complication, see Fig. 14.6. Administering the radiation to the breast in the dependent position (patient is prone) reduces this complication. See Fig. 14.7. Prone positioning has been shown to have several advantages: (i) Similar long-term controls as supine (traditional) positioning (ii) Improves dose homogeneity (iii) Is sparing of cardiac/lung tissue (iv) There is decreased exposure to chest tissue in large-breasted women (v) Better cosmesis
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FIGURE 14.5 Ablative and palliative radiotherapy of the lung. Axial and coronal dose distribution in ablative (A, B) and palliative (C, D) treatment. Doses are represented up to 50% of the prescription dose. Source: Marcareno M, Vagge S. Belgioia L, et al. Ablative or palliative stereotactic body radiotherapy with helical tomotherapy for primary or metastatic lung tumor. Anticancer Res 2013;33:655e60.
FIGURE 14.6 Radiation pneumonitis following radiotherapy to breast. A 58-year-old woman with a history of stage I cancer in the right breast (T1N0M0, according to the tumorenodeemetastasis classification) presented with a 2-week history of shortness of breath and cough. Eight months before presentation, she had undergone lumpectomy and adjuvant radiotherapy to the affected breast. Over a period of 5 weeks, the patient had been treated with a total dose of 50 Gy of radiation over the targeted field, which included breast parenchyma and a portion of the anterior lung, as shown on computed tomography (CT) with superimposed isodose lines (Panel A). The radiotherapy had ended 6 months before presentation. Subsequent CT showed typical features of radiation pneumonitis, which included consolidation in a nonanatomical distribution that did not conform to lobes or bronchopulmonary segments (Panel B). Many air bronchograms are visible with slight dilatation of peripheral bronchi, which often progresses to traction bronchiectasis. Although pneumonitis occurs mainly within the irradiated areas of the lung, it may spread to nonirradiated areas. The patient was given prednisolone at a dose of 100 mg once a day for 3 days, with the dose then slowly reduced, and her symptoms resolved after 5 weeks of treatment (Panel C). Source: Boelke E, Matuschek C. Radiation pneumonitis after radiotherapy for breast cancer. N Engl J Med 2009;361:e65.
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14.3 Recommended regimens for common malignancies
(A)
FIGURE 14.7
(B)
A radiotherapy to the breast. (A) prone and supine positions. (B) traditional supine position.
These advantages become even more pronounced with larger breasts [37].
14.3.4 Carcinoma of prostate External beam irradiation and isotope insertions (“brachytherapy”) are both used as primary treatments for early carcinoma of the prostate. They are reported to be as effective as surgery (see in Chapter 12). Anatomical precision is important because radiation damage to adjacent organs, especially the rectum, can occur.
(A)
Brachytherapy has reached a very advanced level of sophistication in the last 10 years due to improvements in ultrasound imaging of the prostate during the procedure (allowing direct visualization of the deposition of the seeds) and better computer-assisted planning and seed delivery methods. The great advantage of brachytherapy is that it is a single procedure, a small operation, with the patients almost always leaving hospital next day. The inclusion of patients for brachytherapy is defined by relatively strict criteria. Usually,
(B)
‘Trains’ of seeds already implanted
Prostate gland
Urethra
Bladder
Implant needle
Template through which implant needles are guided Rectum
FIGURE 14.8
Endorectal ultrasound probe directing needle to correct position
A conventional radiotherapy versus brachytherapy for prostate cancer. (A) Conventional radiotherapy. Axial CT scan through pelvis with an IMRT isodosimetric plan superimposed and the high dose regions dose-washed in turquoise and red. Note the ability of the IMRT technique to cause a concavity in the high dose region such that the rectum (pink) is spared from the high dose radiotherapy. (B) Brachytherapy. Sagittal view of the Seattle low dose radiation seed implant technique for prostate cancer with the transrectal probe in situ and the implant taking place via the transperineal route through a template (seen “side-on” in the main diagram but “en face” in the “bubble” top right), the depth coordinate being called by the rectal ultrasound probe. Sources: (A) London Prostate Cancer Treatment Center. https://www.prostatecancertreatment.co.uk/treatmentoptions/radiotherapy/. (B) https://www.prostatecancertreatment.co.uk/treatment-options/brachytherapy/.
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(A)
(B)
Involved-field
(A2)
Extended-field
Total nodal irradiation
FIGURE 14.9 (A) Radiation fields used in Hodgkin’s disease. Radiation fields previously used in Hodgkin’s disease, mantle, para-aortic, and inverted Y fields. (B) Current irradiation: involved field, extended field, and total node irradiation in a patient with left cervical involvement of Hodgkin’s lymphoma (clinical stage 1). Individual nodes are imaged and irradiated in continuity with adjacent node-rich areas, where subimaging-sized deposits may be present. Source: (A) Research Gate. https://www.researchgate.net/figure/Radiation-therapy-fields-in-the-treatment-of-classical-Hodgkin-lymphoma_fig1_221924026.
candidates have a biopsy-proven Gleason score less than 8, a gland of less than 50cc, good urinary flow rates, and a PSA of less than 15 (Fig. 14.8).
lymphomas are frequently treated with external beam irradiation [38] (Fig. 14.9).
14.3.5 Hematological malignancies
14.3.6 Gamma knife radiosurgery for tumor deposits in the brain
Radiation therapy is part of the bone marrow ablation phase of stem cell transplantation for leukemia. Hodgkin’s disease and extranodal
This is a sharply focused form of multiport gamma irradiation, used especially to treat tumors of the brain. The achievement of the
References
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References
Gamma rays
Target
Gamma Knife unit and radiation delivery
FIGURE 14.10 Gamma knife stereotactic radiosurgery. Gamma knife stereotactic radiosurgery technology uses many small gamma rays to deliver a precise dose of radiation to the target. Source: Mayo Clinic. https://www. mayoclinic.org/tests-procedures/brain-stereotactic-radiosurgery/ about/pac-20384679.
anatomical precision of the technique relates to prior work on minimally invasive stereotactic surgery of the brain [39]. Radiosurgery for tumor treatment works by damaging or destroying the DNA of tumor cells so that these cells cannot reproduce or grow. Over time, the brain tumor shrinks [40]. Studies are showing gamma knife radiosurgery (GKRS) to be a safe and effective treatment for both large vestibular schwannoma (VS) and for residual and recurrent VS after microsurgery [41]. GKRS is most commonly used to treat brain tumors (both benign and malignant), arteriovenous malformations, trigeminal neuralgia, acoustic neuroma, and pituitary tumors [42] (Fig. 14.10).
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[18] Curtis HJ. Formal discussion of: somatic mutation and carcinogenesis. Cancer Res 1965;25(8):1305e8. [19] Morgan WF, Murnane JP. A role for genomic instability in cellular radioresistance? Cancer Metastasis Rev 1995; 14(1):49e58. [20] Nenoi M. Current topics in ionising radiation Research. New Delhi: InTech Publications; 2012. [21] National Association for Proton Therapy. Proton Therapy Centers in the US. https://www.proton-therapy. org/map/. [22] Cancer Research UK. Proton beam therapy is arriving in the UK: what does that mean for patients?. July 2017. https://scienceblog.cancerresearchuk.org/2017/ 07/17/proton-beam-therapy-is-arriving-in-the-uk-whatdoes-that-mean-for-patients/. [23] DeLaney TF, Kooy HM. Proton and charged particle radiation therapy. Philadelphia: LWW/WoltersKluwer; 2008. [24] Ma C-MC, Lomax T, editors. Proton and carbon ion therapy (imaging in medical diagnosis and therapy. Boca Raton: CRC Press; 2013. [25] Schulz-Ertner D, J€akel O, Schlegel W. Radiation therapy with charged particles. Semin Radiat Oncol 2006; 16:249e59. [26] Brenner DJ, Hall EJ. Secondary neutrons in clinical proton radiation therapy: a charged issue. Radiother Oncol 2008;86(2):165e70. [27] Strander H, Turesson I, Cavallin-Ståhl E. A systematic overview of radiation therapy effects in soft tissue sarcomas. Acta Oncol 2003;42(5e6):516e31. [28] Elgqvist J, Frost S, Pouget PJ, et al. The potential and hurdles of targeted alpha therapy e clinical trials and beyond. Front Oncol 2014;14(3):324. [29] Karar J, Maity A. Modulating the tumor microenvironment to increase radiation responsiveness. Cancer Biol Ther 2009;8(21):1994e2001. [30] Wang AZ, Tepper JE. Nanotechnology in radiation oncology. J Clin Oncol 2014;32(26):2879e85. [31] Purdy JA. Principles of radiologic physics, dosimetry and treatment planning. In: Perez CA, Brady LW, Halpern EC, et al., editors. Principles and practice of radiation oncology. 4th ed. Philadelphia: LWW/WoltersKluwer; 2004. p. 180e218.
[32]
[33]
[34] [35]
[36]
[37]
[38]
[39] [40]
[41]
[42]
Cancer Research UK. General side effects of radiotherapy. https://www.cancerresearchuk.org/ about-cancer/cancer-in-general/treatment/radiotherapy/side-effects/general-radiotherapy/about. Salvo N, Doble B, Khan L, et al. Prophylaxis of radiation-induced nausea and vomiting using 5hydroxy-tryptamine-3 seratonin receptor antagonists: a systematic review of randomized trials. Int J Radiat Oncol Biol Phys 2012;82(1):408e17. Hall EJ. Is there a place for quantitative risk assessment? J Radiol Prot 2009;29(2A):A171e84. Subroto P, Lee PC, Mao J, et al. Long-term survival with stereotactic ablative radiotherapy (SABR) versus thoracoscopic sublobar lung resection in elderly people: national population based study with propensity matched comparative analysis. BMJ 2016;354. American Cancer Society. Radiation therapy for colorectal cancer. https://www.cancer.org/cancer/colonrectal-cancer/treating/radiation-therapy.html. Image-Guided Radiation Therapy. Prone breast radiation therapy. http://www.igrt.com/breast-therapy. html. Specht L, Yahalom J, Illidge T, et al. Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the international lymphoma radiation oncology group (ILROG). Int J Radiat Oncol Biol Phys 2014;89(4):854e62. Heilbrun MP, editor. Stereotactic neurosurgery. Baltimore: Williams and Wilkins; 1988. Suero ME, van Eck ATCJ, Sauerland C, et al. Local tumor control and clinical symptoms after gamma Knife radiosurgery for residual and recurrent vestibular schwannomas. World Neurosurgery 2019;122: e1240e6. ISSN 1878-8750, https://doi.org/10.1016/j. wneu.2018.11.022. Columbia Neurological Society. Gamma knife radiosurgery. https://www.columbianeurosurgery.org/ treatments/gamma-knife-radiosurgery/. Mayo Clinic. Brain stereotactic radiosurgery. https:// www.columbianeurosurgery.org/treatments/gammaknife-radiosurgery/.
14 Aspects of radiation therapy O U T L I N E 14.1 General 376 14.1.1 Units of therapeutic radiation and absorption 376 14.1.2 Aspects of kinds of damage; differences according to species and kinds of cells 376 (a) Species 377 (b) Cells 378 14.1.3 Oxygen effect 378 14.1.4 Hyperthermia as a possible adjunct in radiation and chemotherapy distinct from thermal ablation 378 14.1.5 Radiation therapy enhancing metastasis 378 14.1.6 Specific issues in radiations acting on genomic stability in cells 379 14.2 Aspects of particular forms of radiation therapy 379 14.2.1 Electron beam radiation therapies 379 14.2.2 Nuclear particle beams 379 (a) Protons in comparison with high energy radiations 379 (b) Neutrons 381
The history of radiation therapy, like that of radiology, began shortly after the discovery of X-rays by Roentgen in 1895. Two modes were
Principles of Tumors https://doi.org/10.1016/B978-0-12-816920-9.00014-6
(c) Helium nuclei (a-rays) (d) “Heavy” ions: carbon nuclei
14.2.3 Radio-sensitizers and protectors 14.2.4 Aspects of applications in the clinic (a) Anatomical precision (b) Treatment of regular side effects (c) Limitations to total doses of radiation therapy (d) Protection of radiation therapy staff
381 381
381 381 381 382 382 383
14.3 Recommended regimens for common malignancies 383 14.3.1 Carcinoma of lung 383 14.3.2 Carcinoma of the colon and rectum383 14.3.3 Carcinoma of breast 383 14.3.4 Carcinoma of prostate 385 14.3.5 Hematological malignancies 386 14.3.6 Gamma knife radiosurgery for tumor deposits in the brain 386 References
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quickly developed: administration by X-ray from electric generators and administration by local application of radium salts [1,2].
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The main principles of radiotherapy for tumors were established in the early 20th century:
tissue as well as the energy carried by the particles of the radiation.
(i) Different sensitivities of different types of tumors (ii) Greater efficacy when given in split dosesd“fractionation” (see in Chapter 13) (iii) Different frequencies of relapses for different types of tumors (iv) Absence of any single target, or cancerspecific target of radiations in tumor cells. Because of this, effective radiotherapy depends on the tumor cells being more sensitive to the treatment than normal cells (v) Cumulative therapeutic limit for normal tissues. Patients cannot tolerate radiotherapy above particular total lifetime doses (see Section 13.1.10) (vi) Predictable side effects.
Incident radiation energy is quantitated in terms of the “Roentgen,” which is the amount of radiation necessary to create by ionization of 1 esu (electrostatic unit) of electricity in 1 cm3 of air under standard conditions. Absorbed radiation energy in any structure can be referred to in units called “rads” (radiation absorbed dose), or as more often as “Gray” (100 rads ¼ 1Gy). To account for differences between tissues (see Appendix A1.1.4), the “rem” (radiation equivalent in man) was devised. It is a complex average of the rads of different tissues and is used in studies of human radiation tolerances and damage. The unit now widely used is the “Sievert” (100rem ¼ 1 Sievert). “Linear energy transfer” (LET) is the rate of energy transfer per unit distance (e.g., keV/ mm) that a particular kind of radiation deposits in a particular matter or structure. It is mainly used in experimental studies of radiation damage. The relationships between LET and RBE (relative biological effect) differ between different tissues. This is made more difficult by problems of defining and quantitating “effect” in different biological systems. Therapeutically, radiations generally only affect cells exposed to them. They have little or no effect on cells outside the irradiated field, except perhaps by the “bystander effect” [4]. Recurrences may therefore arise for reasons similar to those seen after attempted cure by surgical resection (see Fig. 14.1).
With the invention of higher-energy X-ray machines, radium applications and other isotope methods fell into disuse, although, recently, the principle has been reintroduced as “brachytherapy” for treatment especially of carcinoma of the prostate [3] and some other organs. This chapter describes the features which are important for their therapeutic uses.
14.1 General 14.1.1 Units of therapeutic radiation and absorption In physics, energy can be indicated in terms of the electron volt (eV), being the energy absorbed or lost by the charge on an electron moved by 1 volt of electric potential difference. In medicine, units of energy deposition have been derived in relation to tissue damage reflecting that (i) Only absorbed energy has any effect on the tissues. (ii) The proportion of the energy in the incident radiations which is absorbed by the tissue or part of the body depends on the kind of
14.1.2 Aspects of kinds of damage; differences according to species and kinds of cells Radiations in different doses can produce most of the known genopathic and nongenopathic effects (see in Appendix A7). Commonly in high short-term dosages, radiations regularly cause
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14.1 General
Incident rays
Absorption and scatter of rays Air
30cm of tissue
Photons Ultraviolet rays: Penetrate a few mm; no scatter of secondary rays ‘Soft’ X-rays: Superficial maximum absorbance; penetrate 10-20 cm, no significant scatter of secondary rays ‘Hard’ X-rays: Deeper maximum absorbance, pass through human body (as for diagnostic imaging); moderate scatter. Gamma rays: Deeper maximum absorbance, considerable penetration; greater scatter.
= depth at which maximum rate of absorption/unit length of path occurs.
“Scatter”
“Scatter” and secondary photonic radiations
Electrons Penetration up to 5 cm depending on energy. No scatter. Protons 20-30 cm penetration, Most energy deposited at termination (similar shape as ‘Bragg peak’ of photons in air), Litter scatter of the protons occurs, but seconday photonic radiations are generated.
FIGURE 14.1
Secondary photonic radiations
Absorption, penetration, and scatter for different particles and different energies (EVs) in water (most tissues
are similar).
nongenopathic effects, especially inflammation of tissues and acute cell death. At lower doses given over longer periods of time, radiations cause mild inflammation and tissue atrophy. Many of these effects are variable between the different species which are used experimentally. (a) Species There are enormous differences in the radioresistance of species according to evolutionary complexity (see also Appendix A3.5.1). There is
a well-recognized ascending order of radiosensitivity from certain bacteria, through unicellular organisms such as amebae, invertebrates, and vertebrates, and then mammals, which are the most sensitive organisms. Within each category of organisms, strains have been developed by in-breeding which have greater or lesser degrees of radio-sensitivity. This indicates that some genomic factor(s), probably acting through a gene product, are associated with radiosensitivity.
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(b) Cells In general, the most sensitive cells are those in which fully specialized versions are continuously produced from local tissue stem cells. These “labile tissues” include the bone marrow and gastrointestinal epithelium (see also Appendix A1.3.3). The least sensitive cells are those of tissues which do not depend on a specific stem cell population. These “stable” kinds of cells include fibrocytes and adipocytes (see Appendix A1.4.1). The mitotic rate is thought to be a major factor in these differences [5].
14.1.3 Oxygen effect In the late 1940s, it was found that oxygenation enhances chromosomal aberrations in irradiated cells [6]. Other studies showed that in many models, cell killing due to radiation therapy is increased in hyperoxic conditions [7]. This is consistent with oxygen being the most important atom from which reactive species can be generated by radiation therapy (see Section 4.3). It should be noted that oxygen effects are only seen with radiation therapies. There is no oxygen effect with any of the common cytotoxic drugs used in nonsurgical anticancer therapy. These agents do not use oxygen as an intermediary source of toxic products. Attempts have been made to enhance tumor cell sensitivity by hyperbaric oxygen treatment to the patient. The results have generally been disappointing, although interest for these procedures continues [7]. Hypoxia induces a variety of responses in cells. One response is production of a transcription factor (hypoxia-inducible factor 1, HIF-1) which enhances production of a number of other proteins. Inhibitors of HIF-1 are potentially useful enhancers of radiation-induced cell killing [8]. As another factor, hypoxic cells may lack energy due to deficiencies in the respiratory enzyme cycle. These cells, although not dead,
may be subviable/under “cell stress” (see Appendix A7.1.7). For these cells, oxygen therapy may not assist in limiting tumor cell growth.
14.1.4 Hyperthermia as a possible adjunct in radiation and chemotherapy distinct from thermal ablation Temperatures in the range 40e45 C sensitize cells to radiations and chemotherapy [9,10]. For radiation therapy, possible mechanisms may include the following: (i) The tissue-heating effect of radiations raises the temperature in the tumor masses to the lethal range (above 45 C) and (ii) Increased ionization of atoms occurs because the electron-energizing effects of radiations are greater at higher temperatures. In relation to drugs, the chemical reactions of these agents with cellular macromolecules may be increased by increased temperatures. As a different form of treatment, raising tumor temperature over 45 C kills all cells directly and is used in the procedure known as thermal ablation, to destroy tumors [11], including in situ tumors.
14.1.5 Radiation therapy enhancing metastasis Radiation therapy induces acute inflammation in all vascular tissues (see in Appendix A7). Blood vessels and lymphatic vessels dilate and more fluid flows through them. Any tumor cells in those vessels are therefore more likely to be carried along to sites of metastasis. Radiation therapy is known to increase the numbers of circulating tumor cells [12]. If those cells derive from the irradiated tumor, they are likely to be dead, and of no consequence. However, some of the cells may be in transit outside the radiation field and be viable. These cells could then be flushed to the systemic circulation by the
14.2 Aspects of particular forms of radiation therapy
inflammatory exudates more rapidly than they would be otherwise. In this, it may be remembered that radiations only affect the cells which are exposed to them, although in some experimental conditions, a “by-stander effect” can be demonstrated [13]. This could kill cells in transit outside the radiation field. Recently, it has been suggested that radiation therapy can enhance the spread of metastases in the body [14]. The issue could be investigated further, possibly by assessing the viability of the tumor cells circulating postradiation treatment.
14.1.6 Specific issues in radiations acting on genomic stability in cells It has long been known that radiations can induce genomic events, such as chromosomal aberrations and heritable phenotypic changes (mutations) [15]. However, the idea that radiation administered to parent cells could lead to progressive genomic instability in daughter cells is relatively recent [16e18]. Genomic instability might usefully increase tumor cell loss in the short term. However, it might later lead to radio-resistant strains in surviving cells, with radiation- and chemical resistance, and even overall shorter patient survival [19].
14.2 Aspects of particular forms of radiation therapy 14.2.1 Electron beam radiation therapies Electrons in beams have only slight penetrance of tissues but are useful against some superficial skin tumors [20]. Electrons are the effective agency of the isotope used in treatment of thyroid cancers. Iodine125 decays into tellurium with the release of eight low energy electrons, but not gamma rays. The same isotope is also used for brachytherapy (direct introduction into tumor masses of sealed sources of radiation) for carcinoma of
379
the prostate. This isotope of iodine is cytotoxic and causes chromosomal aberrations but is not known to be carcinogenic (cf 131I, which emits gamma rays and beta particles).
14.2.2 Nuclear particle beams For a given amount of absorbed energy, nuclear particle radiations cause more tissue damage than photonic radiations. This has created interest in their possible superiority as therapeutic agents against tumors. Machines have been developed to emit protons, neutrons, helium nuclei (a rays), and carbon nuclei in beams. However, at the time of writing, only protonbeam irradiation is being used regularly for tumor therapy. In the United States, there are 14 operative proton therapy centers and a further 10 are under construction [21]. There is a small number in the United Kingdom and elsewhere. Only approximately 1% of cancers are suitable to this mode of treatment. There is little convincing evidence that for many patients, the treatment is significantly more effective than conventional photonic radiation therapy [22]. (a) Protons in comparison with high energy radiations Protons deposit their energy in broader tracks but have lower penetrations of tissues than photons [21e24]. The benefit of beams of photons over beams of high-energy photons lies in the fact that in tissues, protons deliver energy with a peak at a particular depth (often referred to as a “Bragg peak,” while electron beams deposit energy in a slowly attenuating distribution with depth (see Fig. 14.1)). When used for treating tumors, the proton beams are adjusted so that peak energy deposition occurs in the tumor. Multiple portals are generally used (from 2 to 4) [25]. The existence of the peak results in relatively little damage to the tissues deep to the tumor. As mentioned above, photons cause greater damage to tissues compared with electrons for
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the same amount of deposited energy. This phenomenon can be understood in terms of the absorption of energy by the two forms of radiation. Because photons have low masses, the ejection of an electron from an outer shell of an atom probably requires approximately eight photons of sufficient energy moving in the same direction to strike within a short period of time (Fig. 14.2). The energy of these photons is absorbed in the one ionization event. Other ionizing events are scattered at random in the tissue.
Photons
On the other hand, due to their relatively high mass, protons only lose part of their energy in an ionizing event. After one such event, a proton can continue in its path causing multiple lesions in a line. This line can include sites in the one macromolecule, so that this clustered damage causes greater effects (Fig. 14.2). As a result, proton beams inflict more chromosomal damage and more lethality per unit energy deposited, compared with photonic radiations [21]. All nuclear particle rays can displace nuclear particles from irradiated atoms, especially
Protons
At level of electron shell
Outer electron energy level of atom Additive effects of at least eight high energy photons (as in X-rays and gamma rays, are required to ionize an atom (in biology, mainly of oxygen)
A single energized nuclear particle is sufficient to ionize an atom (in biology, mainly of oxygen)
At level of molecules Direction of rays
The energy of the photons is absorbed by the ionizing event, so that these photons cause little further damage. Low numbers of ionizing events in a molecule may not affect its structure, so that the function of the complex of which it is part may not be affected.
FIGURE 14.2
Direction of rays
The energy of the proton is only slightly reduced by the ionizing collision, so that it continues in a path causing further ionizations. High numbers of ionizing events in a molecule are likely to affect its structure, so that the function of a complex of which it is part may be affected.
Basis of different biological effects of photonic and nuclear particle radiations.
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14.2 Aspects of particular forms of radiation therapy
“secondary neutrons.” The significance of this is at present unclear [26].
Bronchoscope
Oesophagus (gullet)
(b) Neutrons These rays, especially with high energy levels (“fast neutrons”), have less penetration of tissues but inflict more damage on tissues for the energy deposited than X-rays. In clinical trials, neutron beams produced more damage to normal tissues than X-rays, and without better effects on the tumor tissues [27]. (c) Helium nuclei (a-rays) These rays have very low penetration of air and tissues and are used in clinical practice via administered isotopes rather than as beams [28]. (d) “Heavy” ions: carbon nuclei These are not currently in wide use and are undergoing trials in a few centers only. At the time of writing, their superiority over X-ray therapies is unclear [25].
14.2.3 Radio-sensitizers and protectors A variety of physical agents (e.g., heat and chemicals) have been suggested to assist cell killing by radiation therapy. They include conventional cytotoxic drugs, as well as those which act through hypoxia-related phenomena [7,29]. Another group comprises inhibitors such as misonidazole, of radical-scavenging chemicals, especially thiols. Recently, metal-containing nanoparticles have been studied in this role [30] (Fig. 14.3).
14.2.4 Aspects of applications in the clinic (a) Anatomical precision The principle of radiation therapy is to deliver the maximum dose of radiation to the tumor cells for the minimum damage to normal tissues.
Trachea (windpipe)
Catheter Radioactive source Tumour
FIGURE 14.3 Internally administered radiation therapy. Source: WikiCommons, Cancer Research UK.
The precision of delivery of the radiations depends on accurate prior knowledge of the anatomical extent of the tumor. This involves understanding of the shape of the tumor mass in three dimensions. However, the demarcation between the tumor and the adjacent apparently normal tissue may be blurred because there may be micrometastases and intravascular tumor deposits beyond the macroscopic (and imaging) margins of the main tumor mass (Fig. 14.4). In practice, anatomical precision of radiation delivery from inserted pellets of radio-isotopes directly into tumor tissue (“brachytherapy”) is reasonably easy. However, for external beam irradiation, complicated equipment is required. In a typical machine, the source of the beam is located on circular gantry, can be rotated around the patient’s body, and as well, can be moved up and down (toward the head or feet). The beam source can also be angled in any direction with the “cylinder” of the head-to-foot movement of the gantry. Thus, potentially, every part of the body can be irradiated from any angle. The beam can be modified in various ways and changed in shape
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(mainly made more oval) by alterations in the collimator of the beam source [31]. The most modern machines have a computerized tomographic (“CT”) or magnetic resonance imaging (“MRI”) function added to the radiation-source function. With these, it is possible to deliver radiations of the required dose according to the detailed threedimensional images of the tumor in the patient. (b) Treatment of regular side effects Regular local side effects occur because damage to untargeted adjacent tissue is a regular side effect of all radiation therapies. Damage to normal tissue can occur (i) Between the beam source and the tumor, (ii) Beyond the tumor, and also (iii) To the sides of the tumor, by way of “scatter” of radiations. Regular systemic side effects occur because most forms of cytotoxic damage to parts of the body result in tissue breakdown products
entering the circulation. These substances can cause mild malaise and nausea (see in Section 10.4), for example, in myocardial infarction. In radiation therapy, fatigue, nausea, vomiting, and malaise occur in all patients, and often in severe degrees [32]. The mechanisms are not understood. Radiation-killed cells and tissues may release products of greater potency than from unirradiated dead cells, due to the degrees of denaturation of the substances which may occur. Various inflammatory mediators, including 5hydroxytryptamine [33], may play roles in these side effects. Various antinausea drugs and corticosteroids are often given for relief of these symptoms. They do not affect the efficacy of the radiation treatment. (c) Limitations to total doses of radiation therapy These can be classified as local and systemic (see also Section 13.1.11). Local limiting factors to total dose of radiation therapy mainly relate
= recurrent mass of matastatic tumor Focal extension of tumor mass
Other Organs
In principle, this ‘ablative’ radiotherapy has similar limitations to those of surgery: tumor outside the field of irradiation is little affected.
FIGURE 14.4
Sources of recurrences after radiation therapy.
14.3 Recommended regimens for common malignancies
to the site of the tumor. In cases in which the tumor is close to a vital organ or structure in the path of the proposed radiation beams, too much radiation may damage the vital structure. Any concurrent disease in those organs (for example, previous glomerular disease in a kidney in or near the radiation field) must be taken into account. Systemic limiting factors to total possible therapeutic dose include the presence of any other diseases, such as emphysema, heart disease, or renal failure, which would make the patient less able to tolerate radiation therapy.
383
14.3.2 Carcinoma of the colon and rectum Radiation therapy to treat colon cancer in selected cases: (i) Before surgery (along with chemo) to help shrink a tumor and make it easier to remove. (ii) After surgery, if the cancer has attached to an internal organ or the peritoneum. (iii) Rarely, it can be given just before closing the abdomen, to the tumor bed. (iv) Along with chemotherapy as the primary treatment if the patient has comorbidities preventing surgery [36].
(d) Protection of radiation therapy staff Staff members working in radiation therapy departments are often long-term employees. All staff members have protective shielding when in treatment areas and wear exposure monitors when at work. The question of acceptable long-term exposure to radiations is an important, but to a degree controversial, issue (see, e.g., Ref. [34]).
14.3 Recommended regimens for common malignancies 14.3.1 Carcinoma of lung Radiation is most effective against smallcelled carcinoma. In almost all institutions, external beam radiotherapy doses are guided by CT imaging (see in Chapter 11) to deliver the optimum dose to the tumor and the least radiation to normal tissues (intensity-modulated radiation therapy/IMRT). With some machines, it is possible to deliver higher doses (stereotactic body radiation therapydSBRT). With these techniques, the total dose depends directly on the volume of tumor [35] (Fig. 14.5).
14.3.3 Carcinoma of breast Radiations can be delivered by external beam or isotope insertions. It can be given as the primary treatment, but most commonly is used as a postsurgical adjuvant therapy to the bed of the resection (the chest wall following mastectomy). There can be difficulty with anatomical precision, because breast cancers can spread along ducts without forming a mass and in addition be multifocal. The tumor must be unresectable and tethered to prevent movement during irradiation. Radiation pneumonitis is a common complication, see Fig. 14.6. Administering the radiation to the breast in the dependent position (patient is prone) reduces this complication. See Fig. 14.7. Prone positioning has been shown to have several advantages: (i) Similar long-term controls as supine (traditional) positioning (ii) Improves dose homogeneity (iii) Is sparing of cardiac/lung tissue (iv) There is decreased exposure to chest tissue in large-breasted women (v) Better cosmesis
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FIGURE 14.5 Ablative and palliative radiotherapy of the lung. Axial and coronal dose distribution in ablative (A, B) and palliative (C, D) treatment. Doses are represented up to 50% of the prescription dose. Source: Marcareno M, Vagge S. Belgioia L, et al. Ablative or palliative stereotactic body radiotherapy with helical tomotherapy for primary or metastatic lung tumor. Anticancer Res 2013;33:655e60.
FIGURE 14.6 Radiation pneumonitis following radiotherapy to breast. A 58-year-old woman with a history of stage I cancer in the right breast (T1N0M0, according to the tumorenodeemetastasis classification) presented with a 2-week history of shortness of breath and cough. Eight months before presentation, she had undergone lumpectomy and adjuvant radiotherapy to the affected breast. Over a period of 5 weeks, the patient had been treated with a total dose of 50 Gy of radiation over the targeted field, which included breast parenchyma and a portion of the anterior lung, as shown on computed tomography (CT) with superimposed isodose lines (Panel A). The radiotherapy had ended 6 months before presentation. Subsequent CT showed typical features of radiation pneumonitis, which included consolidation in a nonanatomical distribution that did not conform to lobes or bronchopulmonary segments (Panel B). Many air bronchograms are visible with slight dilatation of peripheral bronchi, which often progresses to traction bronchiectasis. Although pneumonitis occurs mainly within the irradiated areas of the lung, it may spread to nonirradiated areas. The patient was given prednisolone at a dose of 100 mg once a day for 3 days, with the dose then slowly reduced, and her symptoms resolved after 5 weeks of treatment (Panel C). Source: Boelke E, Matuschek C. Radiation pneumonitis after radiotherapy for breast cancer. N Engl J Med 2009;361:e65.
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14.3 Recommended regimens for common malignancies
(A)
FIGURE 14.7
(B)
A radiotherapy to the breast. (A) prone and supine positions. (B) traditional supine position.
These advantages become even more pronounced with larger breasts [37].
14.3.4 Carcinoma of prostate External beam irradiation and isotope insertions (“brachytherapy”) are both used as primary treatments for early carcinoma of the prostate. They are reported to be as effective as surgery (see in Chapter 12). Anatomical precision is important because radiation damage to adjacent organs, especially the rectum, can occur.
(A)
Brachytherapy has reached a very advanced level of sophistication in the last 10 years due to improvements in ultrasound imaging of the prostate during the procedure (allowing direct visualization of the deposition of the seeds) and better computer-assisted planning and seed delivery methods. The great advantage of brachytherapy is that it is a single procedure, a small operation, with the patients almost always leaving hospital next day. The inclusion of patients for brachytherapy is defined by relatively strict criteria. Usually,
(B)
‘Trains’ of seeds already implanted
Prostate gland
Urethra
Bladder
Implant needle
Template through which implant needles are guided Rectum
FIGURE 14.8
Endorectal ultrasound probe directing needle to correct position
A conventional radiotherapy versus brachytherapy for prostate cancer. (A) Conventional radiotherapy. Axial CT scan through pelvis with an IMRT isodosimetric plan superimposed and the high dose regions dose-washed in turquoise and red. Note the ability of the IMRT technique to cause a concavity in the high dose region such that the rectum (pink) is spared from the high dose radiotherapy. (B) Brachytherapy. Sagittal view of the Seattle low dose radiation seed implant technique for prostate cancer with the transrectal probe in situ and the implant taking place via the transperineal route through a template (seen “side-on” in the main diagram but “en face” in the “bubble” top right), the depth coordinate being called by the rectal ultrasound probe. Sources: (A) London Prostate Cancer Treatment Center. https://www.prostatecancertreatment.co.uk/treatmentoptions/radiotherapy/. (B) https://www.prostatecancertreatment.co.uk/treatment-options/brachytherapy/.
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(A)
(B)
Involved-field
(A2)
Extended-field
Total nodal irradiation
FIGURE 14.9 (A) Radiation fields used in Hodgkin’s disease. Radiation fields previously used in Hodgkin’s disease, mantle, para-aortic, and inverted Y fields. (B) Current irradiation: involved field, extended field, and total node irradiation in a patient with left cervical involvement of Hodgkin’s lymphoma (clinical stage 1). Individual nodes are imaged and irradiated in continuity with adjacent node-rich areas, where subimaging-sized deposits may be present. Source: (A) Research Gate. https://www.researchgate.net/figure/Radiation-therapy-fields-in-the-treatment-of-classical-Hodgkin-lymphoma_fig1_221924026.
candidates have a biopsy-proven Gleason score less than 8, a gland of less than 50cc, good urinary flow rates, and a PSA of less than 15 (Fig. 14.8).
lymphomas are frequently treated with external beam irradiation [38] (Fig. 14.9).
14.3.5 Hematological malignancies
14.3.6 Gamma knife radiosurgery for tumor deposits in the brain
Radiation therapy is part of the bone marrow ablation phase of stem cell transplantation for leukemia. Hodgkin’s disease and extranodal
This is a sharply focused form of multiport gamma irradiation, used especially to treat tumors of the brain. The achievement of the
References
387
References
Gamma rays
Target
Gamma Knife unit and radiation delivery
FIGURE 14.10 Gamma knife stereotactic radiosurgery. Gamma knife stereotactic radiosurgery technology uses many small gamma rays to deliver a precise dose of radiation to the target. Source: Mayo Clinic. https://www. mayoclinic.org/tests-procedures/brain-stereotactic-radiosurgery/ about/pac-20384679.
anatomical precision of the technique relates to prior work on minimally invasive stereotactic surgery of the brain [39]. Radiosurgery for tumor treatment works by damaging or destroying the DNA of tumor cells so that these cells cannot reproduce or grow. Over time, the brain tumor shrinks [40]. Studies are showing gamma knife radiosurgery (GKRS) to be a safe and effective treatment for both large vestibular schwannoma (VS) and for residual and recurrent VS after microsurgery [41]. GKRS is most commonly used to treat brain tumors (both benign and malignant), arteriovenous malformations, trigeminal neuralgia, acoustic neuroma, and pituitary tumors [42] (Fig. 14.10).
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